Therapeutics for the treatment of glaucoma

ABSTRACT

The present invention provides benzothiadiazine and chroman derivatives and particularly diazoxide and cromakalim derivatives for use in treating glaucoma, retinopathy, treating age related macular degeneration, treating, stabilizing and/or inhibiting blood and lymph vascularization, and reducing intraocular pressure by administering a pharmaceutically effective amount of a prodrug disposed in an ophthalmically acceptable carrier to the eye, wherein the prodrug specifically modulates a KATP channel to reduce an intraocular pressure.

PRIORITY

This application is a continuation of U.S. patent application Ser. No.15/113,773, filed Jul. 22, 2016, which is a National Stage Applicationunder 35 U.S.C. § 371 of International Application No.PCT/US2015/013955, filed Jan. 30, 2015, which claims the benefit of U.S.Provisional Application No. 61/934,310, filed Jan. 31, 2014. Each ofthese references is incorporated in their entirety.

TECHNICAL FIELD OF THE INVENTION

The present invention relates generally to benzothiadiazine and chromanderivatives and particularly diazoxide and cromakalim derivatives andmethods for treating glaucoma and reducing intraocular pressure. It alsorelates to a process for their preparation and pharmaceuticalcompositions in which they are present.

BACKGROUND ART

Without limiting the scope of the invention, its background is describedin connection with methods and compositions for treating glaucoma andreducing intraocular pressure. Glaucoma is a group of conditions, whichcauses a characteristic and progressive optic neuropathy and is theleading cause of irreversible blindness in the world. It is estimatedthat there are 67 million people in the world with glaucoma; 6.7 millionof whom are blind from the condition. There is no cure for glaucoma, acondition which leads to a reduction in visual field and ultimately,legal blindness. Since intraocular pressure is the only modifiable riskfactor/causative agent for glaucoma, treatments focus on reducing theintraocular pressure in the eye to slow glaucoma progression andblindness. Glaucoma is classified according to three parameters, theunderlying cause which is classified as primary (idiopathic) orsecondary (associated with some other ocular or systemic conditions);the state of the anterior chamber angle, classified as open angle (openaccess of the outflowing aqueous humor to trabecular meshwork) or closedangle (narrow angle where the trabecular meshwork is blocked byapposition of the peripheral iris and the cornea); and chronicity, whichmay be acute or chronic. The most common form of glaucoma is primaryopen angle glaucoma.

Treatments for glaucoma range from laser trabeculoplasty to topicaltreatment. For example, selective laser trabeculoplasty is a lasertreatment of the trabecular meshwork as a means to improve the outflowof aqueous humor from the eye, thereby reducing intraocular pressure.Topical treatments are used to slow aqueous humor production or increaseaqueous humor drainage. Both processes will help to decrease intraocularpressure. However, glaucoma medical adherence with topical medication ispoor, and studies suggest that fewer than half of the patients are ableto maintain consistently lowered intraocular pressure with topicalagents. In addition, current intraocular pressure lowering drugs such asbrimonidine, timolol, and prostaglandin analogs can have significantside effects.

U.S. Pat. No. 8,063,054, entitled, “Method of Treatment of RetinalIschemia with Diazoxide” discloses a composition including diazoxide(7-chloro-3-methyl-2H-1,2,4-benzothiadiazine-1,1-dioxide) for thetreatment and/or prevention of retinal ischemia and of diseasesassociated with retinal ischemia. Ischemia is a restriction in bloodsupply to tissues, causing a shortage of oxygen and glucose needed forcellular metabolism (to keep tissue alive). Ischemia is generally causedby problems with blood vessels, with resultant damage to or dysfunctionof tissue. In addition, the compositions are soluble in organicsolvents.

U.S. Pat. No. 7,186,707, entitled, “Prodrugs for use as OphthalmicAgents,” discloses a mechanism by which steroidal quinol compoundsconfer beneficial ophthalmic effects. The subject compounds possess alipophilic-hydrophilic balance for transcorneal penetration and arereadily reduced into parent phenolic A-ring steroid compounds to provideprotection or treatment against various ocular symptoms and disorders.These prodrugs confer lipid solubility optimal for transcornealpenetration and are readily converted to endogenous reducing agents intoactive phenolic A-ring steroid compounds.

U.S. Pat. No. 5,985,856, entitled, “Prodrugs and Methods of Making andUsing the Same,” discloses prodrugs of parent drugs and methods ofmaking and using the same. The prodrugs comprise an amine-containingparent drug moiety and a prodrug moiety, such as methoxyphosphonic acidor ethoxyphosphonic acid. The prodrugs may be employed in therapy forthe treatment of various indications, such as pain, and in methods ofdecreasing the abuse potential of abuse-prone drugs and/or delaying theonset of parent drug activity and/or prolonging parent drug activity ascompared to administration of a parent drug.

U.S. Pat. No. 5,965,620, entitled, “Methods and Compositions forATP-sensitive K+ Channel Inhibition for Lowering Intraocular Pressure,”discloses ATP-sensitive K+ channel modulating compounds are incorporatedinto ophthalmically acceptable carriers for administration to the eye inorder to affect intraocular pressure.

DISCLOSURE OF THE INVENTION

The present invention provides benzothiadiazine and chroman derivativesand particularly diazoxide and cromakalim derivatives for use intreating glaucoma, ocular hypertension, retinopathy, treating agerelated macular degeneration, treating, stabilizing and/or inhibitingblood and lymph vascularization, and reducing intraocular pressure.

The present invention provides a method for reducing intraocularpressure in an eye of a patient by administering a pharmaceuticallyeffective amount of a prodrug disposed in an ophthalmically acceptableaqueous carrier to the eye, wherein the prodrug or released drugspecifically modulates a K_(ATP) channel, wherein the prodrug has theformula:

wherein R9 and R10 may independently be a —H; —CH₂CHCH₃CH₃; —CHCH₃CH₃;—CH₃; —CHCH₃CH₂CH₃; —CH₂(CH₂)₃NH₂; —CH₂CH₂SCH₃; —CH₂OH; or —CHOHCH₃.

The present invention provides a pharmaceutical composition comprising:a benzothiadiazine or chroman derivative disposed in an ophthalmicallyacceptable aqueous carrier. The benzothiadiazine derivative has theformula:

The chroman derivative has the formula:

The present invention provides a method for treating ocular hypertensionand glaucoma in an eye of a patient by identifying a patient sufferingfrom glaucoma in an eye; administering a pharmaceutically effectiveamount of a prodrug disposed in an ophthalmically acceptable carrier tothe eye, wherein the prodrug specifically modulates a K_(ATP) channel toreduce intraocular pressure and treat glaucoma, wherein the prodrug hasthe formula:

wherein R9 and R10 may independently be a —H; —CH₂CHCH₃CH₃; —CHCH₃CH₃;CH₃; —CHCH₃CH₂CH₃; —CH₂(CH₂)₃NH₂; —CH₂CH₂SCH₃; —CH₂OH; or —CHOHCH₃.

The present invention provides a cromakalim derivative compound havingthe formula:

wherein R3 is a prodrug moiety of the formula:

wherein R9 and R10 may independently be a —H; —CH₂CHCH₃CH₃; —CHCH₃CH₃;—CH₃; —CHCH₃CH₂CH₃; —CH₂(CH₂)₃NH₂; —CH₂CH₂SCH₃; —CH₂OH; or —CHOHCH₃.

The present invention provides a diazoxide derivative compound havingthe formula:

wherein R1 or R2 is a prodrug moiety of the formula:

The present invention provides a method for treating glaucoma in an eyeof a patient by identifying a patient suffering from glaucoma or anelevated TOP in an eye; administering a pharmaceutically effectiveamount of a prodrug disposed in an ophthalmically acceptable carrier tothe eye, wherein the prodrug specifically modulates a K_(ATP) channel toreduce intraocular pressure and treat glaucoma, wherein the prodrug hasthe formula:

wherein R9 and R10 may independently be a —H; —CH₂CHCH₃CH₃; —CHCH₃CH₃;CH₃; —CHCH₃CH₂CH₃; —CH₂(CH₂)₃NH₂; —CH₂CH₂SCH₃; —CH₂OH; or —CHOHCH₃. Thedosages are administered from 1 to 4 times per day.

DESCRIPTION OF THE DRAWINGS

For a more complete understanding of the features and advantages of thepresent invention, reference is now made to the detailed description ofthe invention along with the accompanying figures and in which:

FIG. 1A is a graph of a pair of anterior eye segments showing theaddition of CKLP1 (2 μM) that results in the reduction of pressure.

FIG. 1B is a graph of the change in C57BL/6 mice intraocular pressurefollowing treatment with cromakalim in DMSO or CKLP1 in aqueous carrier.

FIG. 2 is a graph of the combination treatment in mice with CKL/CKLP1and prostaglandin showing additive effects. CKL: −12.77±2.38, CKL+LFA:−21.43±1.85 CKLP1: −16.11±2.61, CKLP1+LFA: −26.06±2.98.

FIG. 3 is a graph showing the treatment with various forms of CKL.

FIG. 4 is a graph showing the treatment of rabbits with CKL-P1 in PBS,optically active isomer.

FIG. 5 is a graph showing the treatment with ent-CKLP1 (5 mM).

FIG. 6 is a graph showing the treatment of mice with CKLP1+LFA+U0126.

FIG. 7 is a graph showing the treatment of mice with CKL-P2 (2.5 mM) inPBS.

FIG. 8 is a graph showing the treatment of rabbits with CKL-CF3 in PBS.

FIG. 9 is a graph showing the treatment of mice with PID 3-56 (5 mM inPBS).

FIG. 10 is a graph showing the treatment of mice with PID-37 (5 mM).

FIG. 11 is a graph showing the treatment of mice with PID-57 (5 mM).

FIG. 12 is a graph showing the treatment of mice with PID-257 (5 mM).

FIG. 13 is a graph showing the treatment of mice with PID-298 (5 mM inDMSO).

FIG. 14 is a graph showing the treatment of rabbits with CKL-CF3, CKL-P1in PBS.

FIG. 15 is a graph showing CKLP1 inhibits H₂O₂ oxidative stress.

DESCRIPTION OF EMBODIMENTS

While the making and using of various embodiments of the presentinvention are discussed in detail below, it should be appreciated thatthe present invention provides many applicable inventive concepts thatcan be embodied in a wide variety of specific contexts. The specificembodiments discussed herein are merely illustrative of specific ways tomake and use the invention and do not delimit the scope of theinvention.

To facilitate the understanding of this invention, a number of terms aredefined below. Terms defined herein have meanings as commonly understoodby a person of ordinary skill in the areas relevant to the presentinvention. Terms such as “a”, “an” and “the” are not intended to referto only a singular entity, but include the general class of which aspecific example may be used for illustration. The terminology herein isused to describe specific embodiments of the invention, but their usagedoes not delimit the invention, except as outlined in the claims.

As used herein, an “effective dosage” or “effective amount” of aprodrug, drug, compound, or pharmaceutical composition is an amount thatis expected to be or is sufficient to effect beneficial or desiredresults. For therapeutic use, beneficial or desired results includeresults such as suppressing or reducing the onset and/or development ofa disease or condition or decreasing one or more symptoms resulting froma disease or condition that is responsive to parent drug therapy,including increasing the quality of life of those suffering from adisease or condition responsive to parent drug therapy and/or decreasingthe dose of the same or other medications, drugs, compounds orpharmaceutical compositions required to treat the disease or conditionand/or decreasing or eliminating one or more side effects associatedwith a medication required to treat the individual's disease orcondition. As used herein, “effective dosage” refers to the dosage of aprodrug, drug, compound, or pharmaceutical composition an amountsufficient to accomplish prophylactic or therapeutic treatment eitherdirectly or indirectly. An effective dosage can be administered in oneor more administrations. As is understood in the clinical context, aneffective dosage of a prodrug, drug, compound, or pharmaceuticalcomposition may or may not be achieved in conjunction with another drug,compound, or pharmaceutical composition. Thus, an “effective dosage” maybe considered in the context of administering one or more therapeuticagents, and a single agent may be considered to be given in an effectiveamount if, in conjunction with one or more other agents, a desirableresult may be or is achieved.

As used herein, “pharmaceutically acceptable carrier” includes anymaterial which, when combined with an active ingredient, allows theingredient to retain biological activity. Examples include, but are notlimited to, any of the standard pharmaceutical carriers and any suitableophthalmically acceptable carrier such as a phosphate buffered salinesolution, water, emulsions such as oil/water emulsion, and various typesof wetting agents. Compositions comprising such carriers may beformulated by conventional methods.

As used herein, “parent composition” refers to a composition that doesnot contain a prodrug moiety.

As used herein, “prodrug moiety” or “PM,” refers to any group attachedto a composition that is not present in the parent composition.

As used herein, “prodrug” refers to a derivative of a biologicallyactive compound that may independently have pharmaceutical activity ormay lack pharmaceutical activity but is converted to an active agent. Aprodrug, according to the present invention, may be converted into anactive compound through one or more steps.

As used herein, “pharmaceutically acceptable prodrugs,” refers to thoseprodrugs of the compounds which are, within the scope of sound medicaljudgment, suitable for use in contact with the tissues of humans andlower animals without undue toxicity, irritation, allergic response, andthe like, commensurate with a reasonable benefit/risk ratio, andeffective for their intended use, as well as the zwitterionic forms,where possible, of the compounds of the invention.

As used herein, “Alkyl” refers to linear, branched or cyclic hydrocarbonstructures preferably having from 1 to 20 carbon atoms (a “C₁-C₂₀alkyl”) e.g., 1 to 10 carbon atoms or 1 to 6 carbon atoms. This term isexemplified by groups such as methyl, t-butyl, n-heptyl, octyl,cyclobutylmethyl, cyclopropylmethyl and the like. “Unsubstituted alkyl”refers to an alkyl group that is not substituted with any additionalsubstituents. When an alkyl residue having a specific number of carbonsis named, all geometric isomers having that number of carbons areintended to be encompassed; thus, for example, “butyl” is meant toinclude n-butyl, sec-butyl, isobutyl and t-butyl.

As used herein, “Substituted alkyl” refers to an alkyl group of from 1to 10 carbon atoms, having from 1 to 5 substituents, including but notlimited to, groups such as halogen, alkoxy, acyl, acylamino, acyloxy,amino, hydroxyl, mercapto, carboxyl, aryl, cyano, nitro and the like.For instance, an alkaryl group (alkyl-aryl) is a substituted alkyl andincludes moieties such as propylbenzene where the moiety is attached tothe parent structure via the aryl or the alkyl portion, most preferablyvia the alkyl portion of the substituent.

As used herein, “Alkenyl” refers to linear, branched or cyclichydrocarbon structures preferably having from 2 to 20 carbon atoms (a“C₁-C₂₀ alkenyl”) and more preferably 2 to 10 carbon atoms or 2 to 6carbon atoms and having at least 1 site of alkenyl unsaturation.

As used herein, “Unsubstituted alkenyl” refers to an alkenyl group thatis not substituted with any additional substituents. When an alkenylresidue having a specific number of carbons is named, all geometricisomers having that number of carbons are intended to be encompassed.This term is exemplified by groups such as propen-3-yl (—CH₂—CH═CH₂),3-methyl-but-2-enyl and (═CH₂). The group represented by ═CH₂ indicatesconnectivity from, e.g., an sp2 hybridized carbon atom of a parentstructure to CH₂ via a double bond.

As used herein, “Substituted alkenyl” refers to an alkenyl group,preferably a C₂-C₁₀ alkenyl, having from 1 to 5 substituents, includingbut not limited to, substituents such as halogen, alkoxy, acyl,acylamino, acyloxy, amino, hydroxyl, mercapto, carboxyl, aryl, cyano,nitro and the like.

As used herein, “Alkoxy” refers to the group “alkyl-O—” which includes,by way of example, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy,tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, andthe like.

As used herein, “Substituted alkoxy” refers to the group “substitutedalkyl-O—”.

As used herein, “Alkoxyalkyl” refers to the group “alkyl-O-alkyl-” whichincludes, by way of example, methoxy methyl and the like.

As used herein, “Alkanoate” refers to “alkyl-C(═O)—O—” which includes,by way of example, ethanoate and pentanoate. “Alkyl-Alkanoate” refers to“-alkyl-O—C(═O)alkyl” such as in —CH(CH₂CH₃)—O—C(═O)—CH₃.

As used herein, “Carbonylalkyl” refers to —C(═O)-alkyl, which includes,by way of example, —C(═O)—CH₂CH₃.

As used herein, “Alkoxyphosphonic acid” refers to “alkyl —O—P(═O)(OH)₂”or when referred to or implied as a moiety attached to a parentstructure, the radical “-alkyl-O—P(═O)(OH)₂” such that thealkoxyphosphonic acid is attached to a parent structure via the alkylmoiety. This term is exemplified by groups such as methoxyphosphonicacid and ethoxyphosphonic acid and their radicals—CH₂—O—P(═O)(OH)₂—CH(CH₃)OP(O)(OH)₂ and —CH₂CH₂—O—P(═O)(OH)₂.

As used herein, “Alkylcarbonylalkoxy” refers to alkyl-C(═O)—O-alkyl. Inone variation, the alkylcarbonylalkoxy refers to a moiety C₁-C₄alkyl-C(═O)—O—C₁-C₆ alkyl. An exemplary alkylcarbonylalkoxy is—CH₂CH₂C(═O)OCH₃.

As used herein, “C₃-C₈ monocyclic cycloalkyl” as used herein is a 3-,4-, 5-, 6-, 7- or 8-membered saturated non-aromatic monocycliccycloalkyl ring. Representative C₃-C₈ monocyclic cycloalkyl groupsinclude, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl and cyclooctyl. In one embodiment, the C₃-C₈monocyclic cycloalkyl group is substituted with one or more of thefollowing groups: -halo, —O—(C₁-C₆ alkyl), —OH, —CN, —COOR′, —OC(O)R′,—N(R)₂, —NHC(O)R′ or —C(O)NHR′ groups wherein each R′ is independently—H or unsubstituted —C₁-C₆ alkyl. Unless indicated, the C₃-C₈ monocycliccycloalkyl is unsubstituted.

As used herein, “C₃-C₈ monocyclic cycloalkenyl” as used herein is a 3-,4-, 5-, 6-, 7- or 8-membered non-aromatic monocyclic carbocyclic ringhaving at least one endocyclic double bond, but which is not aromatic.It is to be understood that when any two groups, together with thecarbon atom to which they are attached form a C₃-C₈ monocycliccycloalkenyl group, the carbon atom to which the two groups are attachedremains tetravalent. Representative C₃-C₈ monocyclic cycloalkenyl groupsinclude, but are not limited to, cyclopropenyl, cyclobutenyl,1,3-cyclobutadienyl, cyclopentenyl, 1,3-cyclopentadienyl, cyclohexenyl,1,3-cyclohexadienyl, cycloheptenyl, 1,3-cycloheptadienyl,1,4-cycloheptadienyl, 1,3,5-cycloheptatrienyl, cyclooctenyl,1,3-cyclooctadienyl, 1,4-cyclooctadienyl, or 1,3,5-cyclooctatrienyl. Inone embodiment, the C₃-C₈ monocyclic cycloalkenyl group is substitutedwith one or more of the following groups: -halo, —O—(C₁-C₆ alkyl), —OH,—CN, —COOR′, —OC(O)R′, —N(R′)₂, —NHC(O)R′ or —C(O)NHR′ groups whereineach R′ is independently —H or unsubstituted —C₁-C₆ alkyl. Unlessindicated, the C₃-C₉ monocyclic cycloalkenyl is unsubstituted.

The term “halo” as used herein refers to —F, —Cl, —Br or —I.

The term “3- to 7-membered monocyclic heterocycle” refers to: a 3-, 4-,5-, 6-, or 7-membered aromatic or non-aromatic monocyclic cycloalkyl inwhich 1-4 of the ring carbon atoms have been independently replaced withan NH, an O, or an S moiety. The non-aromatic 3- to 7-memberedmonocyclic heterocycles can be attached via a ring nitrogen, sulfur, orcarbon atom. The aromatic 3- to 7-membered monocyclic heterocycles areattached via a ring carbon atom. Representative examples of a 3- to7-membered monocyclic heterocycle group include, but are not limited tofuranyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl,isothiazolyl, isoxazolyl, morpholinyl, oxadiazolyl, oxazolidinyl,oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl,piperazinyl, piperidinyl, pyranyl, pyrazinyl, pyrazolidinyl,pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole,pyridothiazole, pyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl,quinuclidinyl, tetrahydrofuranyl, thiadiazinyl, thiadiazolyl, thienyl,thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiomorpholinyl,thiophenyl, triazinyl, triazolyl, In one embodiment, the 3- to7-membered monocyclic heterocycle group is substituted with one or moreof the following groups: -halo, —O—(C₁-C₆ alkyl), —OH, —CN, —COOR′,—OC(O)R′, —N(R′)₂, —NHC(O)R′ or —C(O)NHR′ groups wherein each R′ isindependently —H or unsubstituted —C₁-C₆ alkyl. Unless indicated, the 3-to 7-membered monocyclic heterocycle is unsubstituted.

The term “direct administration,” as used herein refers to the compoundsbeing applied topically, or by injection or instillation, into the eye.Such direct administration does not include systemic forms ofadministration, such as oral or parenteral administration, e.g.,intramuscular, subcutaneous, or intraperitoneal injection although thepresent invention may also be administered by this method. Directadministration of the modulating compounds of the present invention isintended to introduce the compounds directly into the eye so that theywill be transported into the anterior chamber where the compounds willbe effective to lower intraocular pressure, by enhancing the transportor release of intraocular fluid from the anterior chamber or bydecreasing fluid production.

The present invention shows both CKLP-1 and its enantiomer are active invivo in eyes. The enantiomer of CKLP1 is referred to as “ent-CKLP1”.CKLP1 can be synthesized from levcromakalim while ent-CKLP1 can besynthesized from (+)-cromakalim.

The methods and compositions of the present invention are also intendedto reduce intraocular pressure conditions of the eye to a point whereoptic nerve damage is slowed. Such conditions may result from a varietyof causes, such as surgery for glaucoma, retinal detachment, uveitis,and the like. The methods and compositions of the present invention relyon administering compounds which specifically modulate, i.e. inhibit orpotentiate the K_(ATP) channel compounds directly to the eye of thepatient or host. In some instances, the compositions may be administeredto reduce the intraocular pressures to below 20 mmHg, or preferablybetween 10-20 mmHg, more preferably between 10-15 mmHg, or between 12-15mmHg.

The K_(ATP) channel is regulated by intracellular adenosine triphosphate(ATP) such that it is spontaneously active in the absence of ATP andclosed by increasing ATP concentration in the cytoplasmic side of themembrane. The K_(ATP) channel is not activated by intraocular Ca⁺², andgating of the channel is independent of membrane potential. K_(ATP)channels are regulated by changes in the intracellular concentration ofATP and have been found in cells from various tissues such as cardiaccells, pancreatic cells, skeletal muscles, smooth muscles, centralneurons and adenohypophysis cells. K_(ATP) channels are found in avariety of different human tissues and have different effects clinicallydepending on that tissue. The K_(ATP) channels have been associated withdiverse cellular functions for example hormone secretion (insulin frompancreatic beta-cells, growth hormone and prolactin from adenohypophysiscells), vasodilation (in smooth muscle cells), cardiac action potentialduration, neurotransmitter release in the central nervous system.

K_(ATP) channels are octamers made up of 4 copies of a K+ inwardrectifying (K_(ir)) subunit (K_(ir) 6.1 or K_(ir) 6.2) and 4 parts of asulfonylurea receptor (SUR) subunit (SUR1, SUR2A, or SUR2B). At least 6different K_(ATP) channels can be made of the different K_(ir) and SURsubunits and thus the K_(ATP) channel openers represent a heterogeneousgroup of compounds. Currently, the known K_(ATP) channel openers havepoor aqueous solubility and are not used in therapeutic application fortreating glaucoma and intraocular pressure. K_(ATP) channel openers havebeen found to relax vascular smooth muscles and have therefore been usedfor the treatment of hypertension. In addition, K_(ATP) channel openerscan be used as bronchodilators in the treatment of asthma and variousother diseases. Furthermore, K_(ATP) channel openers have been shown topromote hair growth, and have been used for the treatment of baldness.K_(ATP) channel openers are also able to relax urinary bladder smoothmuscle and therefore, can be used for the treatment of urinaryincontinence. K_(ATP) channel openers which relax smooth muscle of theuterus can be used for treatment of premature labor. K_(ATP) channelopeners which act on the central nervous system can be used fortreatment of various neurological and psychiatric diseases such asAlzheimer, epilepsy and cerebral ischemia. However, K_(ATP) channelopeners in the prior art have poor aqueous solubility and are generallyunsuited for use in ocular tissues. As a result, the skilled artisanwould generally not study or look to K_(ATP) channels modulators for usein ocular tissues. This is supported by the lack of studies of K_(ATP)channels modulators in ocular tissues. For example, U.S. Pat. No.6,242,443, entitled “1,2,4-benzothiadiazine derivatives, theirpreparation and use’” discloses 1,2,4-benzothiadiazine derivativecompounds useful in the treatment of diseases of the central nervoussystem, the cardiovascular system, the pulmonary system, thegastrointestinal system and the endocrinological system. However, thesecompositions were dissolved in DMSO, added to a buffer and added topancreatic p-cell for testing. In another study Diazoxide was dissolvedin a pure solution of dimethyl sulfoxide (DMSO) and diluted in sterilephysiological serum to obtain a final ophthalmic solution at 0.01%active principle and 0.4% DMSO. Thus the prior art K_(ATP) channelsmodulators are not aqueous soluble and not suitable for use in oculartissues.

The present invention provides aqueous soluble K_(ATP) channelmodulators that function in ocular tissues to reduce intraocularpressure which is both surprising and unexpected as K_(ATP) channelopeners in the prior art have poor aqueous solubility and are generallyunsuited for use in ocular tissues. In addition the aqueous solublebenzothiadiazine and chroman derivative K_(ATP) channel modulators ofthe present invention are effective at concentrations at equal to orlower than the parent composition. For example the benzothiadiazine andchroman derivatives maybe administered at concentrations up to 75% lessthan the parent composition concentration, e.g., 75, 70, 65, 60, 55, 50,45, 40, 35, 30, 25, 20, 15, 10, 5 or incremental variations thereof ofthe concentration of the parent composition.

Compounds useful in the present invention will specifically modulate theK_(ATP) channels in the eye. Thus, a decrease in intraocular pressureoccurs when the eye is treated with K_(ATP) channel openers and nochange in intraocular pressure occurs when the eye is treated withK_(ATP) channel closer.

Some embodiments of the present invention includes diazoxide andcromakalim prodrugs, diazoxide and cromakalim derivative, andsubstituted diazoxide and cromakalim compositions that are aqueoussoluble and function as K_(ATP) channel openers to reduce intraocularpressure. These compositions provide surprising and unexpected resultsas K_(ATP) channel modulators that function in ocular tissues to reduceintraocular pressure.

The present invention includes benzothiadiazine and chroman derivativesthat may be prodrugs and/or derivative compositions, and moreparticularly to diazoxide and cromakalim prodrugs and derivatives, fortreating glaucoma and elevated intraocular pressure. It also relates toa process for their preparation and pharmaceutical compositions in whichthey are present.

The composition also includes prodrugs and/or derivative compositionsthat show activity in the prodrugs and/or derivative form withoutremoval of the prodrug moiety. As such, the prodrug may be administeredwithout need to be converted to an active form to treat glaucoma and/orelevated intraocular pressure. In addition, compositions of the presentinvention are aqueous soluble.

In one embodiment, the present invention includes benzothiadiazine andchroman derivatives and more particularly to diazoxide and cromakalimprodrugs and derivative that are aqueous soluble and can be used totreat glaucoma and elevated intraocular pressure.

In one embodiment, the present invention includes diazoxide andcromakalim prodrugs, diazoxide and cromakalim derivative, andsubstituted diazoxide and cromakalim compositions that are aqueoussoluble and can be used to treat glaucoma and elevated intraocularpressure.

In one embodiment, the present invention provides a series of prodrugsof cromakalim, using both racemic and optically active cromakalim(levcromakalim) as starting materials.

Levcromakalim may also be called(3S,4R)-3-hydroxy-2,2-dimethyl-4-(2-oxopyrrolidin-1-yl)chroman-6-carbonitrileor(3S,4R)-3,4-dihydro-3-hydroxy-2,2-dimethyl-4-(2-oxo-1-pyrrolidinyl)2H-1-benzopyran-6-carbonitrile.Levcromakalim (the optically active cromakalim) is generally referred toas being in the (3S, 4R)-configuration. The ent-CKLP1 would thus be (3R,4S). All compounds tested so far showed biological activity in anormotensive mouse. For example, CKLP1 showed good activity in both themouse and rabbit models and in an ex vivo human eyeball model.

Two phosphate prodrugs were made and tested in racemic forms: rac-CKLP1and rac-CKLP2. CKLP1 has since been synthesized in an optically activeform starting from levcromakalim.

Optically active CKLP1 has been synthesized via the same route startingfrom levcromakalim instead of racemic cromakalim.

The enantiomer of CKLP1, referred to as ent-CKLP1, has been synthesizedfrom the same route starting from (+)-cromakalim.

FIG. 1A is a graph of pressure readings obtained from a pair of humananterior eye segments where one eye was treated with a K_(ATP) channelopener prodrug (CKLP1) while the fellow anterior segment was treatedwith vehicle alone. Results show that addition of CKLP1 (2 μM) reducespressure in human anterior segment perfusion organ culture. FIG. 1B is agraph of pressure change obtained in normotensive C57BL/6 mice followingtreatment with parent (CKL) and prodrug (CKLP1).

FIG. 2 is a graph of the combination treatment in mice with CKL/CKLP1and prostaglandin analog latanoprost free acid (LFA) that shows additiveeffects: −12.77±2.38, CKL+LFA: −21.43±1.85 CKLP1: −16.112.61, CKLP1+LFA:−26.06±2.98.

FIG. 3 is a graph showing the treatment with various forms of CKL. FIG.4 is a graph showing the treatment of rabbits (n=5) with CKL-P1 in PBS,optically active isomer. FIG. 5 is a graph showing the treatment withent-CKLP1 (5 mM). FIG. 6 is a graph showing the treatment of mice (n=10)with CKLP1+LFA+U0126 (shows importance of the ERK pathway-different fromPG analogs). This suggests that CKLP1 works through the Erk1/2 signalingpathway. In the presence of Erk1/2 inhibitor U0126, CKLP1 is not able tolower pressure, while LFA can lower IOP (in mice).

FIG. 7 is a graph showing the treatment of mice (n=5) with CKL-P2 (2.5mM) in PBS.

FIG. 8 is a graph showing the treatment of rabbits (n=5) with CKL-CF3 inPBS.

FIG. 9 is a graph showing the treatment of mice with PID 3-56 (5 mM inPBS). FIG. 10 is a graph showing the treatment of mice with PID-37 (5mM). FIG. 11 is a graph showing the treatment of mice with PID-57 (5mM). FIG. 12 is a graph showing the treatment of mice with PID-257 (5mM). FIG. 13 is a graph showing the treatment of mice with PID-298 (5 mMin DMSO). FIG. 14 is a graph showing the treatment of rabbits (n=5) withCKL-CF3, CKL-P1 in PBS.

FIG. 15 is a graph showing CKLP1 inhibits H₂O₂ oxidative stress. Thepresent invention also provides a CKLP1 composition used to treatneurons; a CKLP1 composition used for neuroprotection; a method ofneuroprotection using a CKLP1 composition; a method of treating neuronsusing a CKLP1 composition; and methods and compositions for thetreatment of ocular hypertension, blindness and loss of vision using aCKLP1 composition. The claimed CKLP1 composition providesneuroprotective properties. As seen in FIG. 15, rat cortical neuronswere treated with 75 μM H₂O₂ for 24 hours with and without CKLP1 and thelevels of lactate dehydrogenase were assayed. CKLP1 inhibited H₂O₂oxidative stress in rat cortical neurons and in turn provides protectionfor the optic nerves. This is significant since current treatments forocular hypertension do not protect the optic nerve, which is the site ofdamage and ultimate vision loss. Therefore, CKLP1 and other prodrugs (asdisclosed herein) may represent the first in class treatment forglaucoma that can treat the main risk factor (elevated intraocularpressure) and also the sight of damage (optic nerve).

In another one embodiment, the present invention provides a series ofprodrugs of levcromakalim conjugated to dipeptides. These dipeptidesincrease solubility and allow the prodrugs to be actively transportedinto the eye via oligopeptide transporters.

The present disclosure provides aqueous-soluble compositions for thetreatment of glaucoma and/or reducing intraocular pressure in patients.One of the compositions is a benzopyrylium derivative which is solublein aqueous solution. For example the composition has the structure:

wherein R¹ is a protecting group and R²-R⁵ are functional groups asdisclosed herein. R¹ may be a nitrile group, alkyl group, haloalkanegroup, fluoroalkane group, nitro group, amine group, carbonylalkylgroup, sulfonyl group, or substituted sulfonyl group. For example R1 maybe a —CN, —CF₃, —CCF₂CF₃, —CF₂CF₃, —CF(CF₃)₂, —NO₂, —NH₂, —COCH₃,

Although R2 is shown above as a substituted monocyclic heterocycle ring,R2 may be a C₃-C₈ member monocyclic heterocycle ring or a substitutedC₃-C₈ member monocyclic heterocycle ring having one or moresubstitutions and/or hetero atoms. For example, R² may be

R3 is shown as a prodrug moiety and may be selected from:

where R9 is a —H group (Gly) and R10 is a —CH₂CHCH₃CH₃ group (Leu);where R9 is a —H group (Gly) and R10 is a —CHCH₃CH₃ group (Val); andwhere R9 and R10 are both a —CHCH₃CH₃ group (Val). In addition, Leu canbe in the D isomer configuration or the L isomer configuration. Theamino acids may include any of the known amino acids, modified aminoacids or non-naturally occurring amino acids and may include 1, 2, 3, 4,5 or more amino acid residues.

Although R4 and R5 are independently shown above as alkyl group, R4 andR5 may independently be a —CH₃, —CH₂F, —OCH₃, —CF₃, —CCF₂CF₃, —CF₂CF₃,—CF(CF₃)₂, —NO₂, —NH₂, —COCH₃, or

Although R6, R7 and R8 are independently shown above as hydrogens eachmay be an alkyl group, a substituted alkyl group, a nitrile functionalgroup, an isothiocyanate group, an isocyanate functional group, athiocyanate functional group, or a trifluoromethyl functional group.

The present disclosure provides aqueous-soluble compositions for thetreatment of glaucoma and/or reducing intraocular pressure in patients.One of the composition is a benzopyrylium, levcromakalim or chroman(3,4-dihydro-2H-1-benzopyran) derivative which is soluble in aqueoussolution. For example the composition has the structure:

R1 R2 R3 R4 R5 —CN

—PM —CH₃ —CH₃ —CF₃

—PM —CH₃ —CH₃ —CCF₂CF₃

—PM —CH₃ —CH₃ —CF₂CF₃

—PM —CH₃ —CH₃ —CF(CF₃)₂

—PM —CH₃ —CH₃

—PM —CH₃ —CH₃ —NO₂

—PM —CH₃ —CH₃ —NO₂

—PM

—CH₃ —CN

—PM —CH₃ —CH₃

wherein R6, R7 and R8 are H and PM is a prodrug moiety selected from:

where R9 is a —H group (Gly) and R10 is a —CH₂CHCH₃CH₃ group (Leu);where R9 is a —H group (Gly) and R10 is a —CHCH₃CH₃ group (Val); andwhere R9 and R10 are both a —CHCH₃CH₃ group (Val). In addition, Leu canbe in the D isomer configuration or the L isomer configuration. Theamino acids may include any of the known amino acids, modified aminoacids or non-naturally occurring amino acids and may include 1, 2, 3, 4,5 or more amino acid residues. It is understood that R1-R8 mayindividually be a functional group selected from Alkyl, Substitutedalkyl, alkenyl, alkoxy, alkoxyalkyl, carbonylalkyl, alkoxyphosphonicacid, alkylcarbonylalkoxy, cycloalkyl, cycloalkenyl, heterocycle, sulfurgroup, halogen, hydrogen, nitrogen group, —CN, —CH₂F, —CF₃, —CF₂CF₃,—CF₂CF₂CF₃.

Specific examples of the aqueous-soluble compositions for the treatmentof glaucoma and/or reducing intraocular pressure in patients includecomposition having the structure:

The compositions may have other protecting groups at the R1 location andstill retain the aqueous solubility, e.g.

In addition, the protecting group may include one or more amino acids.The amino acids may include any of the known amino acids, modified aminoacids or non-naturally occurring amino acids. The specific sequence ororder of the amino acids may be varied as necessary:

wherein R9 and R10 may independently be a —H; —CH₂CHCH₃CH₃; —CHCH₃CH₃;—CH₃; —CHCH₃CH₂CH₃; —CH₂(CH₂)₃NH₂; —CH₂CH₂SCH₃; —CH₂OH; or —CHOHCH₃.Specific levcromakalim derivative examples, include the levcromakalimstructure where R¹ is a —H group (Gly) and R2 is a —CH₂CHCH₃CH₃ group(Leu); where R9 is a —H group (Gly) and R10 is a —CH₂CHCH₃CH₃ group(Leu); where R9 is a —H group (Gly) and R10 is a —CHCH₃CH₃ group (Val);and where R9 and R10 are both a —CHCH₃CH₃ group (Val). In addition, Leucan be in the D isomer configuration or the L isomer configuration. Theamino acids may include any of the known amino acids, modified aminoacids or non-naturally occurring amino acids and may include 1, 2, 3, 4,5 or more amino acid residues.

In addition the linking bonds between the amino acid residues and thecore levcromakalim derivative composition may be varied as necessary,e.g.,

wherein R9 and R10 may independently be a —H; —CH₂CHCH₃CH₃; —CHCH₃CH₃;—CH₃; —CHCH₃CH₂CH₃; —CH₂(CH₂)₃NH₂; —CH₂CH₂SCH₃; —CH₂OH; or —CHOHCH₃.Specific levcromakalim derivative examples, include the levcromakalimstructure where R¹ is a —H group (Gly) and R2 is a —CH₂CHCH₃CH₃ group(Leu); where R9 is a —H group (Gly) and R10 is a —CH₂CHCH₃CH₃ group(Leu); where R9 is a —H group (Gly) and R10 is a —CHCH₃CH₃ group (Val);and where R9 and R10 are both a —CHCH₃CH₃ group (Val). In addition, Leucan be in the D isomer configuration or the L isomer configuration. Theamino acids may include any of the known amino acids, modified aminoacids or non-naturally occurring amino acids and may include 1, 2, 3, 4,5 or more amino acid residues.

The present disclosure provides aqueous-soluble compositions for thetreatment of glaucoma and/or reducing intraocular pressure in patients.For example, the composition has the structure:

and

R1 R2 R3 R4 R5 —CN

—PM —CH₂F —CH₂F —CF₃

—PM —CH₂F —CH₂F —CCF₂CF₃

—PM —CH₂F —CH₂F —CF₂CF₃

—PM —CH₂F —CH₂F

Wherein R6, R7 and R8 are H and PM is selected from:

where R9 is a —H group (Gly) and R10 is a —CH₂CHCH₃CH₃ group (Leu);where R9 is a —H group (Gly) and R10 is a —CHCH₃CH₃ group (Val); andwhere R9 and R10 are both a —CHCH₃CH₃ group (Val). In addition, Leu canbe in the D isomer configuration or the L isomer configuration. Theamino acids may include any of the known amino acids, modified aminoacids or non-naturally occurring aminoacids and may include 1, 2, 3, 4,50r more amino acid residues.

The present disclosure also provides aqueous-soluble compositions forthe treatment of glaucoma and/or reducing intraocular pressureinpatients. One of the composition is a benzopyrylium, levcromakalim orchroman (3,4-dihydro-2H-1-benzopyran) derivative which is soluble inaqueous solution. For example, the composition has the structure:

and

R1 R2 R3 R4 R5 —CN

—PM —CH₃ —CH₃ —CN

—PM —CH₃ —CH₃ —CN

—PM —CH₃ —CH₃ —CN

—PM —CH₃ —CH₃ —CN

—PM —CH₃ —CH₃

Wherein R6, R7 and R8 are H and PM is selected from:

where R9 is a —H group (Gly) and R10 is a —CH₂CHCH₃CH₃ group (Leu);where R9 is a —H group (Gly) and R10 is a —CHCH₃CH₃ group (Val); andwhere R9 and R10 are both a —CHCH₃CH₃ group (Val). In addition, Leu canbe in the D isomer configuration or the L isomer configuration. Theamino acids may include any of the known amino acids, modified aminoacids or non-naturally occurring amino acids and may include 1, 2, 3, 4,5 or more amino acid residues.

The present disclosure provides aqueous-soluble compositions for thetreatment of glaucoma and/or reducing intraocular pressure in patients.For example, the composition has the structure:

and

R1 R2 R3 R4 R5 —CN

—PM —CH₃ —CH₃ —NH₂

—PM —OCH₃ —OCH₃

—PM —CH₃ —CH₃

—PM —CH₃ —CH₃

Wherein R6, R7 and R8 are H and PM is selected from:

where R9 is a —H group (Gly) and R10 is a —CH₂CHCH₃CH₃ group (Leu);where R9 is a —H group (Gly) and R10 is a —CHCH₃CH₃ group (Val); andwhere R9 and R10 are both a —CHCH₃CH₃ group (Val). In addition, Leu canbe in the D isomer configuration or the L isomer configuration. Theamino acids may include any of the known amino acids, modified aminoacids or non-naturally occurring amino acids and may include 1, 2, 3, 4,5 or more amino acid residues.

The present disclosure provides aqueous-soluble compositions for thetreatment of glaucoma and/or reducing intraocular pressure in patients.For example, the composition has the structure:

and

R1 R2 R3 R4 R5 —CF₂CF₃

—PM —CH₃ —CH₃ —CN

—PM —CH₃ —CH₃ —CN

—PM —CH₃ —CH₃

—PM —CH₃ —CH₃ —COCH₃

—PM —CH₃ —CH₃

—PM —CH₃ —CH₃

—PM —CH₃ —CH₃ —CN

—PM —CH₃ —CH₃

Wherein R6, R7 and R8 are Hand R3PM is selected from:

where R9 is a —H group (Gly) and R10 is a —CH₂CHCH₃CH₃ group (Leu);where R9 is a —H group (Gly) and R10 is a —CHCH₃CH₃ group (Val); andwhere R9 and R10 are both a —CHCH₃CH₃ group (Val). In addition, Leu canbe in the D isomer configuration or the L isomer configuration. Theamino acids may include any of the known amino acids, modified aminoacids or non-naturally occurring amino acids and may include 1, 2, 3, 4,5 or more amino acid residues.

The present disclosure provides aqueous-soluble compositions for thetreatment of glaucoma and/or reducing intraocular pressure in patients.For example the composition has the structure:

and

R1 R2 R3 R4 R5 —CN

—PM —CH₃ —CH₃ —NO₂

—PM —CH₃ —CH₃ —CN

—PM —CH₃ —CH₃ —NO₂

—PM —CH₃ —CH₃ —NO₂

—PM —CH₃ —CH₃ —CN

—PM —CH₂F —CH₂F —NO₂

—PM —CH₂F —CH₂F —CN

—PM —CH₂F —CH₂F —NO₂

—PM —CH₂F —CH₂F —NO₂

—PM —CH₂F —CH₂F

Wherein R6, R7 and R8 are Hand PM is selected from:

where R9 is a —H group (Gly) and R10 is a —CH₂CHCH₃CH₃ group (Leu);where R9 is a —H group (Gly) and R10 is a —CHCH₃CH₃ group (Val); andwhere R9 and R10 are both a —CHCH₃CH₃ group (Val). In addition, Leu canbe in the D isomer configuration or the L isomer configuration. Theamino acids may include any of the known amino acids, modified aminoacids or non-naturally occurring amino acids and may include 1, 2, 3, 4,5 or more amino acid residues. It is understood that R1-R8 mayindividually be a functional group selected from Alkyl, Substitutedalkyl, alkenyl alkoxy, alkoxyalkyl, carbonylalkyl, alkoxyphosphonicacid, alkylcarbonylalkoxy, cycloalkyl, cycloalkenyl, heterocycle, sulfurgroup, halogen, hydrogen, nitrogen group, —CN, —CH₂F, —CF₃, —CF₂CF₃,—CF₂CF₂CF₃. In addition, other prodrug moiety or protecting groups maybe used:

where X may be a Alkyl, Substituted alkyl, C₃-C₈ monocyclic cycloalkyl,C₃-C₈ monocyclic cycloalkenyl, 3- to 7-membered monocyclic heterocycle,3- to 7-membered monocyclic heterocycle, e.g., azetidine, azete,oxetane, oxete, thietane, thiete, diazetidine, dioxetane, dioxete,pyrrolidine, pyrrole, tetrahydrofuran, furan, thiolane, thiophene,imidazolidine, imidazole, pyrazolidine, pyrazole, oxazolidine, oxazole,isoxazolidine, isoxazole, isothiazolidine, isothiazole, thiazolidine,thiazole, or substituted variations thereof.

¹H NMR and ¹³C NMR Spectra were recorded on a Bruker 400 spectrometer.The ¹H NMR data are reported as follows: chemical shift in parts permillion downfield of tetramethylsilane (TMS), multiplicity (s=singlet,bs=broad singlet, d=doublet, t=triplet, q=quartet, quint=quintet andm=multiplet), coupling constant (Hz), and integrated value. Couplingconstants listed as J_(31P) disappeared when ¹H NMR spectra were takenwith ³¹P decoupling. The ¹³C NMR spectra were measured with completeproton decoupling. ³¹P NMR spectra taken for compound characterizationwere measured with complete proton decoupling and were referenced to 85%phosphoric acid, which was added to the NMR tube in a sealed capillarytube. LC/MS analysis was carried out using a BEH C₁₈ column (2.1 mm×50mm, 5 um) on a Waters Acquity UPLC system with a Waters ZQ massdetector.

To a stirred suspension of cromakalim (50 mg, 0.175 mmol) in CH₂Cl₂ (5mL) was added 0.45 M tetrazole in acetonitrile (3.9 mL, 1.76 mmol)followed by dibenzyl N,N-dimethylphosphoramidite (0.200 mL, 0.75 mmol).The reaction mixture was stirred at rt for 2.5 h. After cooling themixture in an ice bath, THE (5 mL) was added, followed by drop wiseaddition of 30% H₂O₂ (1 mL). After stirring for 5 min., saturatedaqueous Na₂S₂O₃ (30 mL) was added slowly. The mixture was diluted withwater (50 mL) and extracted with CH₂Cl₂ (2×50 mL). The combined organiclayers were dried (Na₂SO₄), filtered, and concentrated under reducedpressure. Purification by flash chromatography (35% ethylacetate/hexanes) on silica gel followed by a second flash chromatography(60% ethyl acetate/hexanes) on silica gel furnished 89.8 mg product (94%yield) as a clear colorless oil.

To a solution of dibenzyl((3S,4R)-6-cyano-2,2-dimethyl-4-(2-oxopyrrolidin-1-yl)chroman-3-yl)phosphate (65.5 mg, 0.120 mmol) in dry CH₂Cl₂ (3 mL) was added TMSBr (53μL, 0.40 mmol) by syringe. After stirring for 6 hours, the reactionmixture was concentrated under reduced pressure. The resulting residuewas purified by chromatography (0% acetonitrile/20 mM triethylammoniumacetate buffer to 100% acetonitrile, C₁₈ column) to yield 53.5 mg whitesolid after lyophilization. To prepare the sodium salt, a 1 cm widecolumn was filled with 12 cm of DOWEX 50W2 (50-100 mesh) ion exchangeresin. The column was prepared by sequentially washing with 1:1acetonitrile/water, 1M aqueous NaHCO₃, water, and then finally 1:1acetonitrile/water. The reaction product was dissolved in 1:1acetonitrile/water and loaded onto the column, which was eluted with 1:1acetonitrile/water. The product containing fractions were lyophilized tofurnish as a white solid (40.9 mg, 83% yield).

To a solution of cromakalim (188.2 mg, 0.657 mmol) in DMSO (10 mL) wasadded acetic anhydride (10 mL) and acetic acid (6 mL). After stirring atrt for 24 hours, the reaction mixture was diluted with water (400 mL)and carefully neutralized with solid NaHCO₃. The mixture was extractedwith ethyl acetate (3×400 mL). The organic layers were then each furtherextracted with water (400 mL), combined, dried (Na₂SO₄), filtered, andconcentrated under reduced pressure. Purification by flashchromatography (30% to 100% ethyl acetate/hexanes) on silica gelfurnished 202.5 mg of product (89% yield) as a white solid.

To a stirred suspension of(3S,4R)-2,2-dimethyl-3-((methylthio)methoxy)-4-(2-oxopyrrolidin-1-yl)chromane-6-carbonitrile(30.8 mg, 0.089 mmol), phosphoric acid (74.1 mg, 0.756 mmol) and 4 Åmolecular sieves (239 mg) in THF (3 mL) at 0° C., was added a solutionof N-iodosuccinimide (32.9 mg, 0.146 mmol) in THF (1 mL). After warmingto rt over 2 hours, a TLC showed starting material remaining, soadditional NIS was added (37 mg, 0.164 mmol). An hour later, the mixturewas decanted to remove the sieves. Aqueous sodium thiosulfate was addeduntil the color disappeared and then 0.5 mL of 1 M triethylammoniumacetate buffer was added. The THF was removed under reduced pressure andthe resulting residue purified by chromatography (0% acetonitrile/20 mMtriethylammonium acetate buffer to 100% acetonitrile, C18 column) toyield 13.4 mg of brown solid after lyophilization. To prepare the sodiumsalt, a 1 cm wide column was filled with 12 cm of DOWEX 50W2 (50-100mesh, strongly acidic) ion exchange resin. The column was prepared bysequentially washing with 1:1 acetonitrile/water, 1M aqueous NaHCO₃(lots of gas evolution), water, and then finally 1:1 acetonitrile/water.The reaction product was dissolved in 1:1 acetonitrile/water and loadedonto the column, which was eluted with 1:1 acetonitrile/water. Theproduct containing fractions were lyophilized to furnish CKLP2 as awhite solid (7.7 mg, 20% yield).

A suspension of leveromakalim (80.6 mg, 0.281 mmol), DMAP (308.9 mg,2.53 mmol), and Boc-gly-leu-OH (334.7 mg, 1.16 mmol) was stirred for 10min. in DCM (5 mL). HATU (473.7 mg, 1.25 mmol) was added and the mixturestirred at rt. After 24 h., the solvent was removed under reducedpressure and the resulting residue was purified by chromatography (25%to 75% ethyl acetate/hexanes) on silica gel to furnish 103 mg ofBoc-epimer 1, followed by 31.9 mg of Boc-epimer 2, both as waxy whitesolids. Epimer 1:

Boc-epimer 1 (26 mg, 0.047 mmol) was dissolved in 4 M HCl in dioxane (5mL) and stirred for 30 min. The reaction mixture was concentrated underreduced pressure. The resulting residue was purified by chromatography(10% acetonitrile/water with 0.1% formic acid to 100% acetonitrile, C₁₈column) to yield 5.0 mg after lyophilization (21% yield) as a formicacid salt. Epimer 2:

Boc-epimer 2 (18.5 mg, 0.033 mmol) was dissolved in 4 M HCl in dioxane(5 mL) and stirred for 30 min. The reaction mixture was concentratedunder reduced pressure. The resulting residue was purified bychromatography (10% acetonitrile/water with 0.1% formic acid to 100%acetonitrile, C18 column) to yield 4.1 mg after lyophilization (25%yield) as a formic acid salt.

A suspension of leveromakalim (28.7 mg, 0.100 mmol), DMAP (116.9 mg,0.957 mmol), and piperidin-1-yl-acetic acid (49.0 mg, 0.342 mmol) wasstirred for 10 min. in DCM (2 mL). HATU (119.8 mg, 0.315 mmol) was addedand the mixture stirred at rt for 72 h. The reaction mixture wasfiltered and the solvent was removed under reduced pressure. Theresulting residue purified by chromatography (10% to 100% ethylacetate/hexanes) on a RediSep Rf amine column to furnish 39.5 mg ofproduct (96% yield) as a white solid.

A suspension of levcromakalim (26.1 mg, 0.091 mmol), DMAP (125.9 mg,1.03 mmol), and nicotinic acid (42.4 mg, 0.344 mmol) was stirred for 10min. in DCM (2 mL). HATU (109.8 mg, 0.289 mmol) was added and themixture stirred at rt. After 24 h., the solvent was removed underreduced pressure and the resulting residue was purified bychromatography (15% to 100% ethyl acetate/hexanes) on a RediSep Rf aminecolumn, followed by a second flash chromatography (75% to 100% ethylacetate/hexanes) on silica gel to furnish 34.6 mg product (97% yield) asa waxy white solid.

To a solution of(3S,4R)-2,2-dimethyl-3-((methylthio)methoxy)-4-(2-oxopyrrolidin-1-yl)chromane-6-carbonitrile(57.0 mg, 0.165 mmol) in DCE (1.5 mL) was added sulfuryl chloride (0.95mL of 1 M in DCM solution, 0.95 mmol). After stirring for 90 min., thesolvent was removed under reduced pressure and the resulting residue wasleft under vacuum for 10 min. The residue was then dissolved inacetonitrile (1 mL) and a solution of Boc-Gly-Leu-OH (110.8 mg, 0.384mmol) in acetonitrile (3 mL) added by syringe. After 3 h., the solventwas removed under reduced pressure and the resulting residue waspurified by chromatography (30% to 100% ethyl acetate/hexanes) on silicagel to furnish 96.1 mg of product as a white solid (99% yield).

The material from the previous section (42.4 mg, 0.072 mmol) wasdissolved in 4 M HCl in dioxane (2 mL) and stirred for 30 min. Thereaction mixture was concentrated under reduced pressure. The resultingresidue was washed with diethyl ether, which was then discarded. Theremaining material was purified by chromatography (10%acetonitrile/water to 100% acetonitrile, C₁₈ column). The productcontaining fractions were lyophilized after a small amount of dilute HClwas added to them. 8.8 mg white solid (23% yield) as an HCl salt.

To a stirred suspension of the CF₃-analog of cromakalim (161.1 mg, 0.489mmol) in CH₂Cl₂ (15 mL) was added 0.45 M tetrazole in acetonitrile (11.5mL, 5.18 mmol) followed by dibenzyl N,N-dimethylphosphoramidite (0.600mL, 2.26 mmol). The reaction mixture was stirred at rt for 4 h. A TLCshowed remaining starting material so additional dibenzylN,N-dimethylphosphoramidite (0.300 mL, 1.13 mmol) was added and stirringcontinued for an additional 60 min. After cooling the mixture in an icebath, THE (15 mL) was added, followed by dropwise addition of 30% H₂O₂(3 mL). After stirring for 5 min., saturated aqueous Na₂S₂O₃ (60 mL) wasadded slowly. The mixture was diluted with water (100 mL) and extractedwith CH₂Cl₂ (2×150 mL). The combined organic layers were dried (Na₂SO₄),filtered, and concentrated under reduced pressure. Purification by flashchromatography (40% ethyl acetate/hexanes) on silica gel followed by asecond flash chromatography (50% ethyl acetate/hexanes) on silica gelfurnished 182.9 mg product (63% yield) as a clear colorless oil.

To a solution of dibenzyl((3S,4R)-2,2-dimethyl-4-(2-oxopyrrolidin-1-yl)-6-(trifluoromethyl)chroman-3-yl)phosphate (92 mg, 0.156 mmol) in dry CH₂Cl₂ (10 mL) was added TMSBr (250μL, 1.89 mmol) by syringe. After stirring for overnight, the reactionmixture was concentrated under reduced pressure. The resulting residuewas purified by chromatography (0% acetonitrile/20 mM triethylammoniumacetate buffer to 50% acetonitrile, C₁₈ column) to yield 71.5 mg whitesolid after lyophilization. To prepare the sodium salt of X, a 1 cm widecolumn was filled with 12 cm of DOWEX 50W2 (50-100 mesh, stronglyacidic) ion exchange resin. The column was prepared by sequentiallywashing with 1:1 acetonitrile/water, 1M aqueous NaHCO₃ (lots of gasevolution), water, and then finally 1:1 acetonitrile/water. The reactionproduct was dissolved in 1:1 acetonitrile/water and loaded onto thecolumn, which was eluted with 1:1 acetonitrile/water. The productcontaining fractions were lyophilized to furnish CKL-CF3 as a whitesolid (56.4 mg, 80% yield).

The present disclosure also provides aqueous-soluble compositions forthe treatment of glaucoma and/or reducing intraocular pressure inpatients. One of the composition is a Benzothiadiazine derivative whichis soluble in aqueous solution. For example, the composition has thestructure:

or

R1 R2 R3 R4 R5 R6

—CH₃ —H —Cl —H —H

—CH₃ —H —CF₃ —H —H

—CH₃ —H —CH₂F₃ —H —H

—CH₃ —H —CH₂CF₃ —H —H

—H —H —CF₃ —H

—H —H —SO₂NH₂ —Cl —H

—H —H —SO₂NH₂ —CF₃ —H —H —CH₂N(CH₃)₂ —H —Cl —H —H —H —CH₂N(CH₃)₂ —H —CF₃—H —H —H —CH₂N(CH₃)₂ —H —CH₂F₃ —H —H —H —CH₂N(CH₃)₂ —H —CH₂CF₃ —H —H

It is understood that R1-R6 may individually be a functional groupselected from Alkyl, Substituted alkyl, alkenyl, alkoxy, alkoxyalkyl,carbonylalkyl, alkoxyphosphonic acid, alkylcarbonylalkoxy, cycloalkyl,cycloalkenyl, heterocycle, sulfur group, halogen, hydrogen, nitrogengroup, —CN, —CH₂F, —CF₃, —CF₂CF₃, —CF₂CF₂CF₃. Specific example, include:

wherein R1 or R2 is a prodrug moiety of the formula:

In addition, other protecting groups may be used

where X may be a Alkyl, Substituted alkyl, C₃-C₈ monocyclic cycloalkyl,C₃-C₈ monocyclic cycloalkenyl, 3- to 7-membered monocyclic heterocycle,3- to 7-membered monocyclic heterocycle, e.g., azetidine, azete,oxetane, oxete, thietane, thiete, diazetidine, dioxetane, dioxete,pyrrolidine, pyrrole, tetrahydrofuran, furan, thiolane, thiophene,imidazolidine, imidazole, pyrazolidine, pyrazole, oxazolidine, oxazole,isoxazolidine, isoxazole, isothiazolidine, isothiazole, thiazolidine,thiazole, piperidine, or substituted variations thereof.

The present disclosure provides prodrug compositions of the parentcompositions: 3-Benzyloxyamino-7-chloro-4H-1,2,4-benzothiadiazine1,1-dioxide; 7-Chloro-3-methoxyamino-4H-1,2,4-benzothiadiazine1,1-dioxide; 7-Bromo-3-isopropylamino-4H-1,2,4-benzothiadiazine1,1-dioxide;7-Chloro-3-(N-ethyl-N-methylamino)-4H-1,2,4-benzothiadiazine1,1-dioxide; 6-Chloro-3-methoxyamino-4H-1,2,4-benzothiadiazine1,1-dioxide;6-Chloro-3-(1,2,2-trimethylpropyl)amino-4H-1,2,4-benzothiadiazine1,1-dioxide;7-Bromo-3-(1,2,2-trimethylpropyl)amino-4H-1,2,4-benzothiadiazine1,1-dioxide;6-Chloro-3-(N-ethyl-N-methylamino)-4H-1,2,4-benzothiadiazine1,1-dioxide; 5-Amino-7-chloro-3-isopropylamino-4H-1,2,4-benzothiadiazine1,1-dioxide;7-Chloro-3-(1,3-dimethylpentyl)amino-4H-1,2,4-benzothiadiazine1,1-dioxide;7-Chloro-3-(1,5-dimethylhexyl)amino-4H-1,2,4-benzothiadiazine1,1-dioxide;7-Chloro-3-(1,4-dimethylpentyl)amino-4H-1,2,4-benzothiadiazine1,1-dioxide; 5,7-Dichloro-3-isopropylamino-4H-1,2,4-benzothiadiazine1,1-dioxide;7-Bromo-6-trifluoromethyl-3-isopropylamino-4H-1,2,4-benzothiadiazine1,1-dioxide;7-Chloro-3-(3,3-diphenylpropylamino)-4H-1,2,4-benzothiadiazine1,1-dioxide; 7-Chloro-3-(4-phenylbutylamino)-4H-1,2,4-benzothiadiazine1,1-dioxide;7-Chloro-3-(3-diethylamino-1-methylpropylamino)-4H-1,2,4-benzothiadiazine1,1-dioxide; 3-Isopropylamino-4H-1,2,4-benzothiadiazine-5-carboxaldehyde1,1-dioxide; 3-Isopropylamino-4H-1,2,4-benzothiadiazine-7-carboxaldehyde1,1-dioxide; 3-Isopropylamino-4H-1,2,4-benzothiadiazine-6-carboxylicacid 1,1-dioxide; 7-Cyano-3-isopropylamino-4H-1,2,4-benzothiadiazine1,1-dioxide; 6-Chloro-7-iodo-3-isopropylamino-4H-1,2,4-benzothiadiazine1,1-dioxide; 6-Chloro-3-cyanomethylamino-4H-1,2,4-benzothiadiazine1,1-dioxide;5,7-Dichloro-3-isopropylamino-6-trifluoromethyl-4H-1,2,4-benzothiadiazine1,1-dioxide;7-Chloro-3-(3-(1H-imidazol-4-yl)propyl)amino-4H-1,2,4-benzothiadiazine1,1-dioxide; 3-Isopropylamino-6,7-dimethoxy-4H-1,2,4-benzothiadiazine1,1-dioxide;3-(1-Azabicyclo[2.2.2]oct-3-yl)amino-7-chloro-4H-1,2,4-benzothiadiazine1,1-dioxide;6-Chloro-3-(1,2-dimethylpropyl)amino-4H-1,2,4-benzothiadiazine1,1-dioxide;6-Chloro-3-(1,2-dimethylpropyl)amino-7-sulfamoyl-4H-1,2,4-benzothiadiazine1,1-dioxide; 3-Anilino-7-chloro-4H-1,2,4-benzothiadiazine 1,1-dioxide;7-Chloro-3-(imidazol-2-yl)amino-4H-1,2,4-benzothiadiazine 1,1-dioxide;7-Chloro-3-(4-pyridyl)amino-4H-1,2,4-benzothiadiazine 1,1-dioxide;6-Chloro-3-isobutylamino-4H-1,2,4-benzothiadiazine 1,1-dioxide;3-sec-Butylamino-6-chloro-4H-1,2,4-benzothiadiazine 1,1-dioxide;6-Chloro-3-cyclohexylmethylamino-4H-1,2,4-benzothiadiazine 1,1-dioxide;6-Fluoro-3-isopropylamino-4H-1,2,4-benzothiadiazine 1,1-dioxide;3-Cyclopentylamino-6-fluoro-4H-1,2,4-benzothiadiazine 1,1-dioxide;7-Chloro-3-isopropylamino-5-nitro-4H-1,2,4-benzothiadiazine 1,1-dioxide;3-tert-Butylamino-6-chloro-4H-1,2,4-benzothiadiazine 1,1-dioxide;7-Iodo-3-isopropylamino-4H-1,2,4-benzothiadiazine 1,1-dioxide;6-Chloro-7-fluoro-3-isopropylamino-4H-1,2,4-benzothiadiazine1,1-dioxide;3-Isopropylamino-6-trifluoromethyl-4H-1,2,4-benzothiadiazine1,1-dioxide; 7-Chloro-3-cyclopropylmethylamino-4H-1,2,4-benzothiadiazine1,1-dioxide; 3-Isopropylamino-7-methyl-4H-1,2,4-benzothiadiazine1,1-dioxide; 5,7-Dibromo-3-isopropylamino-4H-1,2,4-benzothiadiazine1,1-dioxide; 6-Acetyl-3-isopropylamino-4H-1,2,4-benzothiadiazine1,1-dioxide; 3-Allylamino-6-chloro-4H-1,2,4-benzothiadiazine1,1-dioxide; 6-Chloro-3-(1-ethylpropyl)amino-4H-1,2,4-benzothiadiazine1,1-dioxide; 6-Chloro-3-butylamino-4H-1,2,4-benzothiadiazine1,1-dioxide; 6-Chloro-3-hexylamino-4H-1,2,4-benzothiadiazine1,1-dioxide;6,7-Dichloro-3-(1,2-dimethylpropyl)amino-4H-1,2,4-benzothiadiazine1,1-dioxide;6,7-Dichloro-3-(1-methylbutyl)amino-4H-1,2,4-benzothiadiazine1,1-dioxide;7-Chloro-3-(1,2-dimethylpropyl)amino-2-methyl-2H-1,2,4-benzothiadiazine1,1-dioxide; 6,8-Dichloro-3-isopropylamino-4H-1,2,4-benzothiadiazine1,1-dioxide;7-Chloro-3-isopropylamino-2-methyl-2H-1,2,4-benzothiadiazine1,1-dioxide;3-Isopropylamino-6-benzenesulfonyl-4H-1,2,4-benzothiadiazine1,1-dioxide;3-Isopropylamino-6-methanesulfonyl-4H-1,2,4-benzothiadiazine1,1-dioxide; 5-Chloro-3-isopropylamino-4H-1,2,4-benzothiadiazine1,1-dioxide; 3-Isopropylamino-6-methyl-4H-1,2,4-benzothiadiazine1,1-dioxide;6-Chloro-3-isopropylamino-7-methyl-4H-1,2,4-benzothiadiazine1,1-dioxide;6-Ethoxycarbonylmethyl-3-isopropylamino-4H-1,2,4-benzothiadiazine1,1-dioxide; 6-Carboxymethyl-3-isopropylamino-4H-1,2,4-benzothiadiazine1,1-dioxide; 8-Chloro-3-isopropylamino-4H-1,2,4-benzothiadiazine1,1-dioxide; 6-Isopropyl-3-isopropylamino-4H-1,2,4-benzothiadiazine1,1-dioxide; 7-tert-Butyl-3-isopropylamino-4H-1,2,4-benzothiadiazine1,1-dioxide; 3-Isopropylamino-6-phenoxy-4H-1,2,4-benzothiadiazine1,1-dioxide; 6-Hexyl-3-isopropylamino-4H-1,2,4-benzothiadiazine1,1-dioxide; 6-Cyclohexyl-3-isopropylamino-4H-1,2,4-benzothiadiazine1,1-dioxide;6-(3-Cyclopropyl-1,2,4-oxadiazol-5-yl)methyl-3-isopropylamino-4H-1,2,4-benzothiadiazine 1,1-dioxide;6-Cyanomethyl-3-isopropylamino-4H-1,2,4-benzothiadiazine 1,1-dioxide;7-Chloro-3-(2-phenylethyl)amino-4H-1,2,4-benzothiadiazine 1,1-dioxide;3-sec-Butylamino-7-iodo-4H-1,2,4-benzothiadiazine 1,1-dioxide;7-Iodo-3-(1,2-dimethylpropyl)amino-4H-1,2,4-benzothiadiazine1,1-dioxide;7-Iodo-3-(1,2,2-trimethylpropyl)amino-4H-1,2,4-benzothiadiazine1,1-dioxide; 7-Chloro-3-cyclohexylmethylamino-4H-1,2,4-benzothiadiazine1,1-dioxide;(R)-7-Chloro-3-(1-cyclohexylethyl)amino-4H-1,2,4-benzothiadiazine1,1-dioxide;(S)-7-Chloro-3-(1-cyclohexylethyl)amino-4H-1,2,4-benzothiadiazine1,1-dioxide;(R)-7-Chloro-3-(1-phenylethyl)amino-4H-1,2,4-benzothiadiazine1,1-dioxide;(S)-7-Chloro-3-(1-phenylethyl)amino-4H-1,2,4-benzothiadiazine1,1-dioxide; 3-Cyclohexyimethylamino-7-iodo-4H-1,2,4-benzothiadiazine1,1-dioxide;(R)-3-(1-Cyclohexylethyl)amino-7-iodo-4H-1,2,4-benzothiadiazine1,1-dioxide;(S)-3-(1-Cyclohexylethyl)amino-7-iodo-4H-1,2,4-benzothiadiazine1,1-dioxide; 3-Benzyiamino-7-iodo-4H-1,2,4-benzothiadiazine 1,1-dioxide;(R)-7-Iodo-3-(1-phenylethyl)amino-4H-1,2,4-benzothiadiazine 1,1-dioxide;(S)-7-Iodo-3-(1-phenylethyl)amino-4H-1,2,4-benzothiadiazine 1,1-dioxide;3-sec-Butylamino-7-bromo-4H-1,2,4-benzothiadiazine 1,1-dioxide;7-Bromo-3-(1,2-dimethylpropyl)amino-4H-1,2,4-benzothiadiazine1,1-dioxide; 7-Fluoro-3-isopropylamino-4H-1,2,4-benzothiadiazine1,1-dioxide; 3-sec-Butylamino-7-fluoro-4H-1,2,4-benzothiadiazine1,1-dioxide;7-Fluoro-3-(1,2-dimethylpropyl)amino-4H-1,2,4-benzothiadiazine1,1-dioxide; 7-Bromo-3-cyclopropylamino-4H-1,2,4-benzothiadiazine1,1-dioxide; 7-Chloro-3-cyclobutylamino-4H-1,2,4-benzothiadiazine1,1-dioxide;7-Chloro-3-(2,2,2-trifluoroethyl)amino-4H-1,2,4-benzothiadiazine1,1-dioxide; 3-Isopropylamino-7-nitro-4H-1,2,4-benzothiadiazine1,1-dioxide; 3-Allylamino-7-chloro-4H-1,2,4-benzothiadiazine1,1-dioxide;7-Chloro-3-(2-methoxy-1-methylethyl)amino-4H-1,2,4-benzothiadiazine1,1-dioxide; 7-Chloro-3-(1-ethylpropyl)amino-4H-1,2,4-benzothiadiazine1,1-dioxide; 3-(1-Ethylpropyl)amino-7-iodo-4H-1,2,4-benzothiadiazine1,1-dioxide; 3-sec-Butylamino-7-nitro-4H-1,2,4-benzothiadiazine1,1-dioxide;3-(1,2-Dimethylpropyl)amino-7-nitro-4H-1,2,4-benzothiadiazine1,1-dioxide; 7-Chloro-3-(2-hydroxypropyl)amino-4H-1,2,4-benzothiadiazine1,1-dioxide;7-Chloro-3-(2-hydroxy-1-methylethyl)amino-4H-1,2,4-benzothiadiazine1,1-dioxide; 3-(2-Aminoethyl)amino-7-chloro-4H-1,2,4-benzothiadiazine1,1-dioxide;7-Chloro-3-(2,2-diethoxyethyl)amino-4H-1,2,4-benzothiadiazine1,1-dioxide; 3-Ethylamino-7-fluoro-4H-1,2,4-benzothiadiazine1,1-dioxide; 7-Fluoro-3-propylamino-4H-1,2,4-benzothiadiazine1,1-dioxide; 3-Cyclopropylamino-7-fluoro-4H-1,2,4-benzothiadiazine1,1-dioxide; 3-Cyclobutylamino-7-fluoro-4H-1,2,4-benzothiadiazine1,1-dioxide; 3-Cyclopentylamino-7-fluoro-4H-1,2,4-benzothiadiazine1,1-dioxide; 3-Cyclopropylmethylamino-7-fluoro-4H-1,2,4-benzothiadiazine1,1-dioxide; 3-Allylamino-7-fluoro-4H-1,2,4-benzothiadiazine1,1-dioxide;7-Fluoro-3-(2-methoxy-1-methylethyl)amino-4H-1,2,4-benzothiadiazine1,1-dioxide; 6-Chloro-3-cyclobutylamino-4H-1,2,4-benzothiadiazine1,1-dioxide;6-Chloro-3-(2,2,2-trifluoroethyl)amino-4H-1,2,4-benzothiadiazine1,1-dioxide; 7-Bromo-3-methylamino-4H-1,2,4-benzothiadiazine1,1-dioxide; 7-Bromo-3-ethylamino-4H-1,2,4-benzothiadiazine 1,1-dioxide;7-Bromo-3-cyclobutylamino-4H-1,2,4-benzothiadiazine 1,1-dioxide;7-Bromo-3-(2,2,2-trifluoroethyl)amino-4H-1,2,4-benzothiadiazine1,1-dioxide; 7-Fluoro-3-methylamino-4H-1,2,4-benzothiadiazine1,1-dioxide; 7-Chloro-3-hexylamino-4H-1,2,4-benzothiadiazine1,1-dioxide; 6,7-Dichloro-3-hexylamino-4H-1,2,4-benzothiadiazine1,1-dioxide;3-(2,2-Diethoxyethyl)amino-7-fluoro-4H-1,2,4-benzothiadiazine1,1-dioxide;7-Fluoro-3-(2,2,2-trifluoroethyl)amino-4H-1,2,4-benzothiadiazine1,1-dioxide; 7-Bromo-3-propylamino-4H-1,2,4-benzothiadiazine1,1-dioxide; 6-Chloro-3-cyclopropylmethylamino-4H-1,2,4-benzothiadiazine1,1-dioxide; 3-Cyclopropylmethylamino-7-nitro-4H-1,2,4-benzothiadiazine1,1-dioxide; 7-Nitro-3-propylamino-4H-1,2,4-benzothiadiazine1,1-dioxide; 3-Cyclobutylamino-7-nitro-4H-1,2,4-benzothiadiazine1,1-dioxide; 6,7-Dichloro-3-cyclobutylamino-4H-1,2,4-benzothiadiazine1,1-dioxide; 7-Amino-3-isopropylamino-4H-1,2,4-benzothiadiazine1,1-dioxide; 7-Acetamido-3-isopropylamino-4H-1,2,4-benzothiadiazine1,1-dioxide; 3-Cyclobutylamino-7-methyl-4H-1,2,4-benzothiadiazine1,1-dioxide; 3-Isopropylamino-7-methoxy-4H-1,2,4-benzothiadiazine1,1-dioxide; 7-Methoxy-3-propylamino-4H-1,2,4-benzothiadiazine1,1-dioxide;7-Chloro-3-(2-formylaminoethyl)amino-4H-1,2,4-benzothiadiazine1,1-dioxide;3-(2-Acetylaminoethyl)amino-7-chloro-4H-1,2,4-benzothiadiazine1,1-dioxide; 5-Chloro-3-cyclobutylamino-4H-1,2,4-benzothiadiazine1,1-dioxide; 5-Chloro-3-propylamino-4H-1,2,4-benzothiadiazine1,1-dioxide; 5-Chloro-3-hexylamino-4H-1,2,4-benzothiadiazine1,1-dioxide; 6-Chloro-3-octylamino-4H-1,2,4-benzothiadiazine1,1-dioxide;6-Chloro-3-(1,5-dimethylhexyl)amino-4H-1,2,4-benzothiadiazine1,1-dioxide;3-Isopropylamino-7-trifluoromethyl-4H-1,2,4-benzothiadiazine1,1-dioxide;3-sec-Butylamino-7-trifluoromethyl-4H-1,2,4-benzothiadiazine1,1-dioxide; 3-Isopropylamino-4H-1,2,4-benzothiadiazine-7-carboxylicacid 1,1-dioxide;3-sec-Butylamino-4H-1,2,4-benzothiadiazine-7-carboxylic acid1,1-dioxide; 3-Propylamino-7-trifluoromethyl-4H-1,2,4-benzothiadiazine1,1-dioxide;3-Cyclopropylmethylamino-7-trifluoromethyl-4H-1,2,4-benzothiadiazine1,1-dioxide; 3-Propylamino-4H-1,2,4-benzothiadiazine-7-carboxylic acid1,1-dioxide; 7-Chloro-3-(pyridin-2-yl)amino-4H-1,2,4-benzothiadiazine1,1-dioxide; 3-Ethylamino-6,7-difluoro-4H-1,2,4-benzothiadiazine1,1-dioxide; 7-Fluoro-3,6-di(isopropylamino)-4H-1,2,4-benzothiadiazine1,1-dioxide; 6,8-Difluoro-3-isopropylamino-4H-1,2,4-benzothiadiazine1,1-dioxide; 6,7-Difluoro-3-isopropylamino-4H-1,2,4-benzothiadiazine1,1-dioxide; 6,7,8-Trifluoro-3-isopropylamino-4H-1,2,4-benzothiadiazine1,1-dioxide;7-Fluoro-3-isopropylamino-6-methyl-4H-1,2,4-benzothiadiazine1,1-dioxide;7-Chloro-3-isopropylamino-6-methoxy-4H-1,2,4-benzothiadiazine1,1-dioxide; 6,8-Dichloro-3-ethylamino-4H-1,2,4-benzothiadiazine1,1-dioxide; 6,8-Dichloro-3-propylamino-4H-1,2,4-benzothiadiazine1,1-dioxide; 6,8-Dichloro-3-cyclopropylamino-4H-1,2,4-benzothiadiazine1,1-dioxide;6,8-Dichloro-3-cyclopropylmethylamino-4H-1,2,4-benzothiadiazine1,1-dioxide; 6,8-Dichloro-3-cyclobutylamino-4H-1,2,4-benzothiadiazine1,1-dioxide; 6,8-Dichloro-3-cyclopentylamino-4H-1,2,4-benzothiadiazine1,1-dioxide; 7-Chloro-3-(2-pyridyl)methylamino-4H-1,2,4-benzothiadiazine1,1-dioxide; 7-Chloro-3-(3-pyridyl)methylamino-4H-1,2,4-benzothiadiazine1,1-dioxide; 7-Chloro-3-(4-pyridyl)methylamino-4H-1,2,4-benzothiadiazine1,1-dioxide; 7-Chloro-3-(2-pyridyl)ethylamino-4H-1,2,4-benzothiadiazine1,1-dioxide; 7-Chloro-3-(3-pyridyl)ethylamino-4H-1,2,4-benzothiadiazine1,1-dioxide; 7-Chloro-3-(4-pyridyl)ethylamino-4H-1,2,4-benzothiadiazine1,1-dioxide; 6-Chloro-3-(2-pyridyl)methylamino-4H-1,2,4-benzothiadiazine1,1-dioxide; 6-Chloro-3-(3-pyridyl)methylamino-4H-1,2,4-benzothiadiazine1,1-dioxide; 6-Chloro-3-(4-pyridyl)methylamino-4H-1,2,4-benzothiadiazine1,1-dioxide; 6-Chloro-3-(2-pyridyl)ethylamino-4H-1,2,4-benzothiadiazine1,1-dioxide; 6-Chloro-3-(3-pyridyl)ethylamino-4H-1,2,4-benzothiadiazine1,1-dioxide; 6-Chloro-3-(4-pyridyl)ethylamino-4H-1,2,4-benzothiadiazine1,1-dioxide; 7-Fluoro-3-(2-pyridyl)methylamino-4H-1,2,4-benzothiadiazine1,1-dioxide; 7-Fluoro-3-(3-pyridyl)methylamino-4H-1,2,4-benzothiadiazine1,1-dioxide; 7-Fluoro-3-(4-pyridyl)methylamino-4H-1,2,4-benzothiadiazine1,1-dioxide; 7-Fluoro-3-(2-pyridyl)ethylamino-4H-1,2,4-benzothiadiazine1,1-dioxide; 7-Fluoro-3-(3-pyridyl)ethylamino-4H-1,2,4-benzothiadiazine1,1-dioxide; 7-Fluoro-3-(4-pyridyl)ethylamino-4H-1,2,4-benzothiadiazine1,1-dioxide; 6-Fluoro-3-(2-pyridyl)methylamino-4H-1,2,4-benzothiadiazine1,1-dioxide; 6-Fluoro-3-(3-pyridyl)methylamino-4H-1,2,4-benzothiadiazine1,1-dioxide; 6-Fluoro-3-(4-pyridyl)methylamino-4H-1,2,4-benzothiadiazine1,1-dioxide; 6-Fluoro-3-(2-pyridyl)ethylamino-4H-1,2,4-benzothiadiazine1,1-dioxide; 6-Fluoro-3-(3-pyridyl)ethylamino-4H-1,2,4-benzothiadiazine1,1-dioxide; 6-Fluoro-3-(4-pyridyl)ethylamino-4H-1,2,4-benzothiadiazine1,1-dioxide;6,7-Dichloro-3-(2-pyridyl)methylamino-4H-1,2,4-benzothiadiazine1,1-dioxide;6,7-Dichloro-3-(3-pyridyl)methylamino-4H-1,2,4-benzothiadiazine1,1-dioxide;6,7-Dichloro-3-(4-pyridyl)methylamino-4H-1,2,4-benzothiadiazine1,1-dioxide;6,7-Dichloro-3-(2-pyridyl)ethylamino-4H-1,2,4-benzothiadiazine1,1-dioxide;6,7-Dichloro-3-(3-pyridyl)ethylamino-4H-1,2,4-benzothiadiazine1,1-dioxide;6,7-Dichloro-3-(4-pyridyl)ethylamino-4H-1,2,4-benzothiadiazine1,1-dioxide;6,8-Dichloro-3-(2-pyridyl)methylamino-4H-1,2,4-benzothiadiazine1,1-dioxide;6,8-Dichloro-3-(3-pyridyl)methylamino-4H-1,2,4-benzothiadiazine1,1-dioxide;6,8-Dichloro-3-(4-pyridyl)methylamino-4H-1,2,4-benzothiadiazine1,1-dioxide;6,8-Dichloro-3-(2-pyridyl)ethylamino-4H-1,2,4-benzothiadiazine1,1-dioxide;6,8-Dichloro-3-(3-pyridyl)ethylamino-4H-1,2,4-benzothiadiazine1,1-dioxide;6,8-Dichloro-3-(4-pyridyl)ethylamino-4H-1,2,4-benzothiadiazine1,1-dioxide;6,7-Difluoro-3-(2-pyridyl)methylamino-4H-1,2,4-benzothiadiazine1,1-dioxide;6,7-Difluoro-3-(3-pyridyl)methylamino-4H-1,2,4-benzothiadiazine1,1-dioxide;6,7-Difluoro-3-(4-pyridyl)methylamino-4H-1,2,4-benzothiadiazine1,1-dioxide;6,7-Difluoro-3-(2-pyridyl)ethylamino-4H-1,2,4-benzothiadiazine1,1-dioxide;6,7-Difluoro-3-(3-pyridyl)ethylamino-4H-1,2,4-benzothiadiazine1,1-dioxide;6,7-Difluoro-3-(4-pyridyl)ethylamino-4H-1,2,4-benzothiadiazine1,1-dioxide;6,8-Difluoro-3-(2-pyridyl)methylamino-4H-1,2,4-benzothiadiazine1,1-dioxide;6,8-Difluoro-3-(3-pyridyl)methylamino-4H-1,2,4-benzothiadiazine1,1-dioxide;6,8-Difluoro-3-(4-pyridyl)methylamino-4H-1,2,4-benzothiadiazine1,1-dioxide;6,8-Difluoro-3-(2-pyridyl)ethylamino-4H-1,2,4-benzothiadiazine1,1-dioxide;6,8-Difluoro-3-(3-pyridyl)ethylamino-4H-1,2,4-benzothiadiazine1,1-dioxide;6,8-Difluoro-3-(4-pyridyl)ethylamino-4H-1,2,4-benzothiadiazine1,1-dioxide;6,8-Bis(trifluoromethyl)-3-(1,4-dimethylpentyl)amino-4H-1,2,4-benzothiadiazine1,1-dioxide;6,8-Bis(trifluoromethyl)-3-isopropylamino-4H-1,2,4-benzothiadiazine1,1-dioxide;6,8-Bis(trifluoromethyl)-3-cyclopentylamino-4H-1,2,4-benzothiadiazine1,1-dioxide;6,8-Bis(trifluoromethyl)-3-cyclopropylamino-4H-1,2,4-benzothiadiazine1,1-dioxide;6,8-Bis(trifluoromethyl)-3-propylamino-4H-1,2,4-benzothiadiazine1,1-dioxide;6,8-Bis(trifluoromethyl)-3-cyclobutylamino-4H-1,2,4-benzothiadiazine1,1-dioxide;6.8-Bis(trifluoromethyl)-3-ethylamino-4H-1,2,4-benzothiadiazine1,1-dioxide; 3-isopropylamino-4H-1,2,4-benzothiadiazine 1,1-dioxide;3-isobutylamino-4H-1,2,4-benzothiadiazine 1,1-dioxide;(2-ethylhexylamino)-4H-1,2,4-benzothiadiazine 1,1-dioxide;cyclopropylamino-4H-1,2,4-benzothiadiazine 1,1-dioxide;cyclohexylamino-4H-1,2,4-benzothiadiazine 1,1-dioxide;7-chloro-3-(1,2,2-trimethylpropylamino)-4H-1,2,4-benzothiadiazine1,1-dioxide;7-chloro-3-(1,2-dimethylpropylamino)-4H-1,2,4-benzothiadiazine1,1-dioxide; 7-chloro-3-(1-methylpropylamino)-4H-1,2,4-benzothiadiazine1,1-dioxide; 7-chloro-3-isopropylamino-4H-1,2,4-benzothiadiazine1,1-dioxide; 7-chloro-3-cyclopropylamino-4H-1,2,4-benzothiadiazine1,1-dioxide; 7-chloro-3-cyclohexylamino-4H-1,2,4-benzothiadiazine1,1-dioxide; 6-chloro-3-isopropylamino-4H-1,2,4-benzothiadiazine1,1-dioxide; 6-chloro-3-cyclopropylamino-4H-1,2,4-benzothiadiazine1,1-dioxide; 6,7-dichloro-3-isopropylamino-4H-1,2,4-benzothiadiazine1,1-dioxide; 6,7-dichloro-3-cyclopropylamino-4H-1,2,4-benzothiadiazine1,1-dioxide; 3-isobutylamino-7-methyl-4H-1,2,4-benzothiadiazine1,1-dioxide; 3-cyclopentylamino-7-methyl-4H-1,2,4-benzothiadiazine1,1-dioxide;3-cyclohexylamino-6-trifluoromethyl-4H-1,2,4-benzothiadiazine1,1-dioxide; (N-cyclohexyl-N-methylamino)-4H-1,2,4-benzothiadiazine1,1-dioxide; 3-cyclohexylamino-4-methyl-4H-1,2,4-benzothiadiazine1,1-dioxide; 3-cyclohexylamino-2-methyl-2H-1,2,4-benzothiadiazine1,1-dioxide.

The pharmaceutical composition of the present invention may beformulated into a variety of topically or injectable administrableophthalmic compositions, such as solutions, suspensions, gels,ointments, micelles and emulsions such as water-in-oil emulsion oroil-in-water emulsion, the emulsion being cationic or anionic.

A liquid which is ophthalmically acceptable is formulated such that itcan be administered topically to the eye. The comfort should bemaximized as much as practicable, although sometimes formulationconsiderations (e.g. drug stability, bioavailability, etc.) maynecessitate less than optimal comfort. In the case that comfort cannotbe maximized, the liquid should be formulated such that the liquid istolerable to the patient for topical ophthalmic use. Additionally, anophthalmically acceptable liquid should either be packaged for singleuse, or contain a preservative to prevent contamination over multipleuses.

Usually, said ophthalmic pharmaceutical composition is sterile. Forophthalmic application, solutions or medicaments are often preparedusing a physiological saline solution as a major vehicle. Ophthalmicsolutions are often maintained at a comfortable pH (usually within therange of pH 5.5-8) and an ophthalmically acceptable osmolality(generally about 150-450 mOsm, preferably 250-350 mOsm).

The formulations may also contain conventional, pharmaceuticallyacceptable preservatives, stabilizers and surfactants. Various buffersand means for adjusting pH may be used so long as the resultingpreparation is ophthalmically acceptable. Accordingly, buffers include,but are not limited to, acetate buffers, citrate buffers, phosphatebuffers, tris(hydroxymethyl)aminomethane (Tris) buffers and boratebuffers. Acids or bases may be used to adjust the pH of theseformulations as needed.

In another embodiment, the composition contains a preservative.Preservatives that may be used in the pharmaceutical compositionsdisclosed herein include, but are not limited to, cationic preservativessuch as quaternary ammonium compounds including benzalkonium chloride,polyquad, and the like; guanidine-based preservatives including PHMB,chlorhexidine, and the like; chlorobutanol; mercury preservatives suchas thimerosal, phenylmercuric acetate and phenylmercuric nitrate; andoxidizing preservatives such as stabilized oxychloro complexes.

In another embodiment, the composition contains a surfactant. Asurfactant may be used for assisting in dissolving an excipient or anactive agent, dispersing a solid or liquid in a composition, enhancingwetting, modifying drop size, or a number of other purposes. Usefulsurfactants include, but are not limited to surfactants of the followingclasses: alcohols; amine oxides; block polymers; carboxylated alcohol oralkylphenol ethoxylates; carboxylic acids/fatty acids; ethoxylatedalcohols; ethoxylated alkylphenols; ethoxylated aryl phenols;ethoxylated fatty acids; ethoxylated; fatty esters or oils (animal andveg.); fatty esters; fatty acid methyl ester ethoxylates; glycerolesters; glycol esters; lanolin-based derivatives; lecithin and lecithinderivatives; lignin and lignin derivatives; methyl esters;monoglycerides and derivatives; polyethylene glycols; polymericsurfactants; propoxylated and ethoxylated fatty acids, alcohols, oralkyl phenols; protein-based surfactants; sarcosine derivatives;sorbitan derivatives; sucrose and glucose esters and derivatives.

In particular, ethoxylate surfactants are useful. An ethoxylatesurfactants is one that comprises the moiety —O(CH₂CH₂O)_(n)—OH, whereinn is at least about 1.

Other excipient components which may be included in the ophthalmicpreparations are chelating agents. A useful chelating agent is edetatedisodium, although other chelating agents may also be used in place orin conjunction with it.

The present compositions in the form of aqueous suspensions may includeexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example, sodiumcarboxymethylcellulose, methylcellulose, hydroxypropyl-methylcellulose,sodium alginate, polyvinylpyrrolidone, gun tragacanth and gun acacia;dispersing or wetting agents may be a naturally occurring phosphatide,for example, lecithin, or condensation products of ethylene oxide withlong chain aliphatic alcohols, for example,heptadeca-ethyleneoxycetanol, or condensation products of ethylene oxidewith partial esters derived from fatty acids and a hexitol such aspolyoxyethylene sorbitol mono-oleate, or condensation products ofethylene oxide with partial esters derived from fatty acids and hexitolanhydrides, for example, polyoxyethylene sorbitan mono-oleate, and thelike and mixtures thereof.

In one embodiment of the invention, said pharmaceutical composition asdescribed here above is packaged in the form of unit dose. In oneembodiment, said unit dose is a container capable of dispensing eyedrops such as common manual bulb-operated pipette or small squeezebottle with a dropper tip. In another embodiment, said unit dose is acontainer to which a device for the placement of eye drops may beapplied. In another embodiment, said unit dose is a container capable ofatomizing drops or droplets. In another embodiment, said unit dose is adisposable syringe.

In another embodiment, said pharmaceutical composition as described hereabove is for treating glaucoma. In one embodiment, glaucoma is selectedin the group of primary open angle glaucoma (POAG), primary angleclosure glaucoma, normal tension glaucoma (NTG), pediatric glaucoma,pseudoexfoliative glaucoma, pigmentary glaucoma, traumatic glaucoma,neovascular glaucoma, irido corneal endothelial glaucoma. Primary openangle glaucoma is also known as chronic open angle glaucoma, chronicsimple glaucoma, glaucoma simplex.

In another embodiment, said pharmaceutical composition as described hereabove is for treating retinopathy, especially diabetic retinopathy andretinopathy of prematurity. In another embodiment, the pharmaceuticalcomposition as described here above is for treating age related maculardegeneration. In another embodiment, the pharmaceutical composition asdescribed here above is for treating ocular hypertension includingocular hypertension resulting from trauma or surgery.

It will also be possible to incorporate the aqueous-soluble compositionsof the present invention into controlled-release formulations andarticles, where the total amount of compound is released over time,e.g., over a number of minutes or hours. The term controlled-release isused to define a release profile to effect delivery of an active over anextended period of time, defined herein as being between about 60minutes and about 2, 4, 6 or even 8 hours. Controlled-release may alsobe defined functionally as the release of over 80 to 90 percent (%) ofthe active ingredient after about 60 minutes and about 2, 4, 6 or even 8hours. Controlled-release as used herein may also be defined as makingthe active ingredient available to the patient or subject regardless ofuptake. Typically, the total dosage of the compound will be within thelimits described above for non-controlled-release formulations, but insome cases may be greater, particularly when the controlled releaseformulations act over relatively longer periods of time. Suitablecontrolled release articles for use with the compositions of the presentinvention include solid ocular inserts. Other controlled-releaseformulations may be based on polymeric carriers, including bothaqueous-soluble polymers and porous polymers having desirablecontrolled-release characteristics, e.g., various cellulose derivatives,such as methylcellulose, sodium carboxymethylcellulose,hydroxyethylcellulose, and the like. Suitable porous polymeric carrierscan be formed as polymers and copolymers of acrylic acid, polyacrylicacids, ethylacrylates, methylmethacrylates, polyacrylamides, and thelike. Certain natural biopolymers may also find use, such as gelatins,alginates, pectins, agars, starches, and the like. A wide variety ofcontrolled-release carriers are known in the art and available for usewith the present invention. Topical compositions for delivering theaqueous-soluble compositions of the present invention will typicallycomprise the compound present in a suitable ophthalmically acceptablecarrier, including both organic and inorganic carriers. Exemplaryophthalmically acceptable carriers include water, buffered aqueoussolutions, isotonic mixtures of water and water-immiscible solvents,such as alkanols, arylalkanols, vegetable oils, polyalkalene glycols,petroleum-based jellies, ethyl cellulose, ethyl oleate,carboxymethylcelluloses, polyvinylpyrrolidones, isopropyl myristates,and the like. Suitable buffers include sodium chloride, sodium borate,sodium acetate, gluconates, phosphates, and the like. The formulationsof the present invention may also contain ophthalmically acceptableauxiliary components, such as emulsifiers, preservatives, wettingagents, thixotropic agents (e.g., polyethylene glycols, antimicrobials,chelating agents, and the like). Particularly suitable antimicrobialagents include quaternary ammonium compounds, benzalkonium chloride,phenylmercuric salts, thimerosal, methyl paraben, propyl paraben, benzylalcohol, phenylethanol, sorbitan, monolaurate, triethanolamine oleate,polyoxyethylene sorbitan monopalmitylate, dioctyl sodium sulfosuccinate,monothioglycerol, and the like. Ethylenediamine tetracetic acid (EDTA)is a suitable chelating agent. It will be understood that particularembodiments described herein are shown by way of illustration and not aslimitations of the invention. The principal features of this inventioncan be employed in various embodiments without departing from the scopeof the invention. Those skilled in the art will recognize or be able toascertain using no more than routine experimentation, numerousequivalents to the specific procedures described herein. In addition,the present embodiments are meant to encompass both stereo chemicalstructures and combinations of different stereo chemical structures inthe same composition. Such equivalents are considered to be within thescope of this invention and are covered by the claims.

What is claimed is:
 1. A method to treat increased intraocular pressure,glaucoma, ocular hypertension, retinopathy, or age related maculardegeneration to a host in need thereof comprising administering aneffective amount of a compound of the formula:

optionally in a pharmaceutically acceptable carrier.
 2. The method ofclaim 1, wherein the host is a human.
 3. The method of claim 2 to treatincreased intraocular pressure.
 4. The method of claim 2 to treat ocularhypertension.
 5. The method of claim 2 to treat glaucoma.
 6. The methodof claim 5, wherein the glaucoma is selected from primary open angleglaucoma, primary angle closure glaucoma, normal tension glaucoma,pediatric glaucoma, pseudoexfoliative glaucoma, pigmentary glaucoma,traumatic glaucoma, neovascular glaucoma, and irido corneal endothelialglaucoma.
 7. The method of claim 6, wherein the glaucoma is primary openangle glaucoma.
 8. The method of claim 6, wherein the glaucoma ispediatric glaucoma.
 9. The method of claim 6, wherein the glaucoma isneovascular glaucoma.
 10. The method of claim 6, wherein the glaucoma isnormal tension glaucoma.
 11. The method of claim 2 to treat retinopathy.12. The method of claim 11, wherein the retinopathy is diabeticretinopathy.
 13. The method of claim 2 to treat age related maculardegeneration.
 14. The method of claim 2, wherein the compound is of theformula:


15. The method of claim 2, wherein the compound is of the formula:


16. The method of claim 14 to treat increased intraocular pressure. 17.The method of claim 14 to treat ocular hypertension.
 18. The method ofclaim 14 to treat glaucoma.
 19. The method of claim 18, wherein theglaucoma is selected from primary open angle glaucoma, primary angleclosure glaucoma, normal tension glaucoma, pediatric glaucoma,pseudoexfoliative glaucoma, pigmentary glaucoma, traumatic glaucoma,neovascular glaucoma, and irido corneal endothelial glaucoma.
 20. Themethod of claim 19, wherein the glaucoma is primary open angle glaucoma.21. The method of claim 19, wherein the glaucoma is pediatric glaucoma.22. The method of claim 19, wherein the glaucoma is neovascularglaucoma.
 23. The method of claim 19, wherein the glaucoma is normaltension glaucoma.
 24. The method of claim 14 to treat retinopathy. 25.The method of claim 24, wherein the retinopathy is diabetic retinopathy.26. The method of claim 14 to treat age related macular degeneration.27. The method of claim 15 to treat increased intraocular pressure. 28.The method of claim 15 to treat ocular hypertension.
 29. The method ofclaim 15 to treat glaucoma.
 30. The method of claim 29, wherein theglaucoma is selected from primary open angle glaucoma, primary angleclosure glaucoma, normal tension glaucoma, pediatric glaucoma,pseudoexfoliative glaucoma, pigmentary glaucoma, traumatic glaucoma,neovascular glaucoma, and irido corneal endothelial glaucoma.
 31. Themethod of claim 30, wherein the glaucoma is primary open angle glaucoma.32. The method of claim 30, wherein the glaucoma is pediatric glaucoma.33. The method of claim 30, wherein the glaucoma is neovascularglaucoma.
 34. The method of claim 30, wherein the glaucoma is normaltension glaucoma.
 35. The method of claim 15 to treat retinopathy. 36.The method of claim 35, wherein the retinopathy is diabetic retinopathy.37. The method of claim 15 to treat age related macular degeneration.